Hematopoiesis

Sruthi Pillai

TSEC

Introduction

primary lymphoid organs - development and maturation of lymphocytes

secondary lymphoid organs - trap antigen and interact

Hematopoiesis

Stem cells totipotent, self renewal

Potency – totipotent, multipotent/pluripotent, unipotent

All blood cells arise from hematopoietic stem cell (HSC)

Hematopoiesis - The formation and development of red and white blood cells

Every functionally specialized, mature blood cell is derived from the same type of stem cell

Hematopoiesis

Site for hemotopoiesis:

Period of gestation

Site Role

1st week embryonic yolk

sac

yolk-sac stem cells differentiate into primitive erythroid cells that contain

embryonic hemoglobin

3rd month – 7th month

fetal liver and then

to the spleen

major roles in hematopoiesis from the third to the seventh months of gestation

From 7th month onwards

Bone marrow major factor in hematopoiesis, and by

birth there is little or no hematopoiesis in the liver and spleen

Hematopoiesis

Study of hematopoietic stem cells is difficult because:

Scarcity (one HSC per 5 x 104 cells in the bone marrow)

hard to grow in vitro

hematopoietic stem cells are maintained at stable levels throughout adult life self renewal

HSCs enormous proliferative capacity.

E.g. mice hematopoietic system destroyed by X rays will die within 10 days

Infused with normal bone-marrow cells from a syngeneic mouse (0.01%–0.1% of the normal amount) restores normal hematopoietic system

Hematopoiesis

Hematopoiesis

Multipotent stem cell HSC differentiates along one of two pathways: Lymphoid progenitor cell

Myeloid progenitor cell

In this step, HSC transform into

progenitor cells loose capacity for

self-renewal and are committed

to a particular cell lineage.

Control its differentiation: Growth factors in its

microenvironment

Hematopoiesis

Lymphoid progenitor cells give rise to

B cells,

T cells,

NK (natural killer) cells

Dendritic cells

Myeloid stem cells generate progenitors of

red blood cells (erythrocytes),

many of the various white blood cells (neutrophils, eosinophils, basophils, monocytes, mast cells, dendritic cells),

platelets

Hematopoiesis

Hematopoiesis

In bone marrow - hematopoietic cells grow and mature on a meshwork of stromal cells (non hematopoietic )

Stromal cells include : fat cells, endothelial cells, fibroblasts, and macrophages.

Stromal cells provide - hematopoietic-inducing microenvironment (HIM)

The required growth factors some are water soluble diffuse through stromal cells reach target

The ones which are not soluble membrane bound

Hematopoiesis Studied In Vitro

Hematopoietic cytokines required for proliferation, differentiation:

1. Colony-stimulating factors (CSFs)

2. Erythropoietin (EPO)

Hematopoiesis Regulated at the Genetic Level

Development of pluripotent hematopoietic stem cells into different cell types requires expression of different sets of lineage-determining and lineage-specific genes

For this study: “knockout mice” a gene has been inactivated or “knocked out” by targeted disruption

Knockout technology is one of the most powerful tools available for determining the roles of particular genes

Many transcription factors that play important roles in hematopoiesis. E.g. GATA-2, Ikaros

Hematopoietic Homeostasis

Production of mature cells = its loss.

erythrocyte - life span -120 days

Neutrophils - few days

T lymphocytes - 20–30 years

To maintain steady-state levels, the average human being must produce an estimated 3.7 x1011 white blood cells per day

Steady-state regulation: Control of the levels and types of cytokines

The production of cytokines with hematopoietic activity by other cell types, such as activated T cells and macrophages

Removal of some cells by cell death

Programmed Cell Death – Homeostatic mechanism